Cardiovascular diseases remain the leading cause of human mortality, one of the most significant causes of this phenomenon is atherosclerosis and high blood level of low-density lipoproteins. Atherosclerosis is a chronic cardiovascular disease in which an artery wall thickens as a result of connective tissue growth, formation of atherosclerotic plaques, lumen narrowing and tissue ischemia.
Abnormal regulation of cholesterol production causes severe pathologies. When total cholesterol production (synthesized and ingested cholesterol) exceeds the amount, necessary for construction and repair of membranes and generation of bile acids and steroids, the accumulation of cholesterol in vessels (atheromatosis) can cause vascular occlusion (atherothrombosis). Cardiovascular pathology is caused by high cholesterol level and especially by high level of low-density lipoproteins (LDL).
The modern opinion on atherosclerosis is that it is a chronic inflammatory disease. Therefore, anti-inflammatory drugs like aspirin, which also has antiplatelet properties, as well as angiotensin-converting-enzyme inhibitors and anti-inflammatory cytokines, are useful for patients suffering from atherosclerosis.
Hypertension is often associated with atherosclerotic damage of vascular wall and, therefore, research, aimed at studying the effect of antihypertensive drugs on the development of atherosclerosis, is important. According to some studies, calcium antagonists have anti-atherogenic properties, as evidenced by the prevention of atherosclerotic damage manifestation. Angiotensin-converting-enzyme inhibitors also exert anti-atherogenic effect in animal experiments. Calcium antagonists verapamil and amlodipine exert anti-atherogenic effect, suppressing serum-induced cellular proliferation, protein synthesis and cholesterol accumulation in cells. Both drugs reduce the severity of atherosclerosis, exhibiting anti-atherosclerotic and anti-atherogenic activity in cell culture. On the contrary, perindopril does not affect atherosclerotic parameters while propranolol even stimulates cholesterol accumulation, proliferative activity of cells and protein synthesis. According to some authors [9], data, obtained using cell cultures, can reflect the in vivo situation. Studies of patients with coronary atherosclerosis treated with calcium antagonists or propranolol have shown, that the latter inhibits atherogenesis to a degree in these conditions. Based on the performed research the authors have made the following ranking of efficacy of the examined drugs: amlodipine>verapamil>perindopril>propranolol.
Among drugs, widely used for treating atherosclerosis, are statins, such as lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin.
It is important to note, that the mechanism of action of statins is associated with inhibiting a speed-limiting stage of cholesterol biosynthesis—conversion of β-hydroxy-β-methyl-glutaryl-CoA (HMG-CoA) to mevalonate, which is catalyzed by the enzyme HMG-CoA reductase.
Research [10] has shown that, despite the success of statin use in effectively reducing cholesterol levels and reducing mortality in cardiovascular diseases, damage of coronary vessels was still observed in about two thirds of patients treated with statins.
Another promising venue of atherosclerosis treatment, besides, for example, raising the level of high-density lipids, is an inhibition of systemic and vascular inflammation process [8].
Currently, combinations of drugs are used to treat atherosclerosis, because monotherapy is not possible. The main reason of this is the absence of a compound, possessing the most optimal spectrum of pharmacological activity: anti-inflammatory, antiplatelet, antihypertensive and hypocholesterolemic. The search for such a molecule is an important goal of pharmacology.
During the last 15 years the understanding of the functioning of different biological systems has changed. It was discovered that nitric oxide (NO), a low-molecular compound, is one of the universal and necessary regulators of cellular metabolism functions. Nitric oxide participates in regulating vascular tone, inhibits platelet aggregation and adhesion on blood vessel walls, and is involved in central and vegetative nervous system, regulating the activity of respiratory organs, gastrointestinal tract and urinary system. Nitric oxide plays an important role in neurotransmission, immune system regulation and protection of the organism from bacterial infections.
Nitric oxide is known to be a potent inhibitor of platelet aggregation. Nitric oxide generation preserves the blood flow by inhibiting thrombogenesis. Factors, regulating the generation and utilization of NO in endogenous conditions, are important in ensuring normal functioning of the cardiovascular system.
In light of the abovementioned, it is important for modern pharmacology to find compounds, able to stimulate the production of nitric oxide as an agent, that inhibits spontaneous and induced platelet aggregation. Thus, in the present study, the search for new effective compounds, which may be useful in medical practice, is based on synthesis and biological research of new nitric oxide generators, which are not structurally analogous to the known NO donors.
Some compounds in indolinone-3 series are known to have antihypertensive activity [2, 4, 5, 6] and being able to generate nitric oxide [1], but there are no compounds in this series, known to be able to activate the soluble guanylate cyclase enzyme and exert antiplatelet action.